When food is present in the alimentary canal, cells in the gut secrete a hormonal signal (an “incretin”), which sensitizes the pancreas to the presence of glucose and results in a potentiated glucose-dependent insulin secretory response. Such a synergistic response to provide glucose-dependent insulin release (Kieffer T J and Habener, J R (1999) Endocr. Rev. 20, 876-913) is seen for the incretin signals, Glucagon-like Peptide 1 (GLP1) and Glucose-dependent Insulinotropic Peptide (GIP). These incretin signals typically exhibit short duration of action in the body, with GLP1 exhibiting at ½ of approximately 1-2 minutes (Knudsen, L B 2004, J. Med. Chem. 47, 4128-34). GLP1 and GIP are cleaved by an amino peptidase, dipeptidyl peptidase IV (DPPIV) and thus, the naturally occurring native hormone is not generally used in medicinal formulations. A peptide found in the saliva of the Gila Monster (exendin 4, Exenatide, Byetta; Amylin Pharmaceuticals, San Diego, Calif.) was shown to bind to the GLP1 receptor and exhibit potent agonistic activity, thereby imparting a desirable glucose-dependent insulin secretory response (Nielsen L L, Young, A A, Parkes, D G (2004) Regul. Peptides, 117, 77-88). Exenatide and analogs of GLP1 have been administered to patients in need of treatment for type 2 diabetes.
Pituitary Adenylate Cyclase-Activating Peptide (PACAP) is a neuromodulatory peptide which stimulates PAC1, VPAC1, and VPAC2 receptors, and is emitted from nerve endings in the pancreas. Receptors of this general class reside in multiple tissues in the body, including in the pancreas (Vaudry D, et al. (2000). Pharmacol Rev 52: 269-324). Administration (infusion) of PACAP to human volunteers or to rodents causes potentiated glucose-dependent insulin secretion, but also results in hyperglycemia (Filipsson K, Tornoe K, Holst J and Ahren B (1997). J Clin Endocrinol Metab 82: 3093-8). In contrast, Vasoactive Intestinal Polypeptide (VIP) activates only the VPAC1 and VPAC2 receptors. In the pancreas, stimulation of the VPAC2 receptors has been shown to provide a potentiated, glucose-dependent insulin release in response to elevated blood glucose levels similar to that of GLP1 or exenatide (Tsutsumi, M., et al. (2002) Diabetes 51, 1453-60). Thus such a stimulus (from PACAP or VPAC agonistic analogs) could be synergistic or alternative to incretin-like signals in stimulating glucose-dependent insulin release, since a similar profile of potentiated insulin secretion results from activation of a second class of receptor. Such an effect would be beneficial in the treatment of metabolic disorders, including Type 2 Diabetes Mellitus (T2DM), metabolic acidosis, insulin resistance and obesity. However, the lack of blood glucose lowering by PACAP in vivo is thought to be related to its ability to cause gluconeogenesis in the liver and release of glucagon. These activities, as well as several side effects, are believed to be caused by activation of PAC1 and VPAC1 receptors. In addition, the naturally occurring native sequence of PACAP and its analogs also are typically short-lived in the body.
Although the reptile GLP1 like molecules (exendin-4, heliodermin, heliospectrin) are longer acting than the mammalian incretins, synthetic exendin-4 (Byetta) remains a relatively short acting peptide (t½ 2 hr in man) and there is a medical need for longer-acting peptides that can modulate glucose-dependent insulin secretion.